Editing Polycystic ovary syndrome (section)

== Cause ==
PCOS is a [[heterogeneous disorder]] of uncertain cause.<ref name="Fauser2011">Page 836 (Section:''Polycystic ovary syndrome'') in: {{cite journal | vauthors = Fauser BC, Diedrich K, Bouchard P, Domínguez F, Matzuk M, Franks S, Hamamah S, Simón C, Devroey P, Ezcurra D, Howles CM | title = Contemporary genetic technologies and female reproduction | journal = Human Reproduction Update | volume = 17 | issue = 6 | pages = 829–847 |date= 2011 | pmid = 21896560 | pmc = 3191938 | doi = 10.1093/humupd/dmr033 }}</ref><ref name="FertSter_molecular">{{cite journal | vauthors = Legro RS, Strauss JF | title = Molecular progress in infertility: polycystic ovary syndrome | journal = Fertility and Sterility | volume = 78 | issue = 3 | pages = 569–576 | date = September 2002 | pmid = 12215335 | doi = 10.1016/S0015-0282(02)03275-2 | doi-access = free }}</ref> There is some evidence that it is a [[genetic disease]]. Such evidence includes the familial clustering of cases, greater [[Concordance (genetics)|concordance]] in [[monozygotic twin|monozygotic]] compared with [[dizygotic]] twins and heritability of endocrine and metabolic features of PCOS.<ref name="Endo2006">{{cite journal |vauthors=Diamanti-Kandarakis E, Kandarakis H, Legro RS |date=August 2006 |title=The role of genes and environment in the etiology of PCOS |journal=Endocrine |volume=30 |issue=1 |pages=19–26 |doi=10.1385/ENDO:30:1:19 |pmid=17185788 |s2cid=21220430}}</ref><ref name="Fauser2011" /><ref name="FertSter_molecular" /> There is some evidence that exposure to higher than typical levels of [[androgens]] and the [[anti-Müllerian hormone]] (AMH) ''in utero'' increases the risk of developing PCOS in later life.<ref>{{cite journal | vauthors = Filippou P, Homburg R | title = Is foetal hyperexposure to androgens a cause of PCOS? | journal = Human Reproduction Update | volume = 23 | issue = 4 | pages = 421–432 | date = July 2017 | pmid = 28531286 | doi = 10.1093/humupd/dmx013 | doi-access = free }}</ref>

It may be caused by a combination of genetic and environmental factors.<ref name="De2016">{{cite journal |vauthors=De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F |date=July 2016 |title=Genetic, hormonal and metabolic aspects of PCOS: an update |journal=Reproductive Biology and Endocrinology |type=Review |volume=14 |issue=1 |page=38 |doi=10.1186/s12958-016-0173-x |pmc=4947298 |pmid=27423183 |doi-access=free }}</ref><ref name="Endo2006" /><ref name="Du2015">{{cite journal |vauthors=Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS |date=October 2015 |title=Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome |journal=Endocrine Reviews |type=Review |volume=36 |issue=5 |pages=487–525 |doi=10.1210/er.2015-1018 |pmc=4591526 |pmid=26426951}}</ref> Risk factors include [[obesity]], a lack of physical exercise, and a family history of someone with the condition.<ref name="NICHD What causes PCOS?">{{cite web |title=What causes PCOS? |url=https://www.nichd.nih.gov/health/topics/pcos/conditioninfo/causes |website=[[Eunice Kennedy Shriver National Institute of Child Health and Human Development]] |date=29 September 2022 |access-date=13 October 2021 |archive-date=9 October 2021 |archive-url=https://web.archive.org/web/20211009211200/https://www.nichd.nih.gov/health/topics/pcos/conditioninfo/causes |url-status=live }}</ref> Diagnosis is based on two of the following three findings: [[anovulation]], high androgen levels, and [[ovarian cysts]].<ref name="NIH2017Def" /> Cysts may be detectable by [[ultrasound]].<ref name="NICHD How do health care providers diagnose PCOS?">{{cite web |title=How do health care providers diagnose PCOS? |url=https://www.nichd.nih.gov/health/topics/pcos/conditioninfo/diagnose |website=[[Eunice Kennedy Shriver National Institute of Child Health and Human Development]] |date=29 September 2022 |access-date=13 October 2021 |archive-date=9 October 2021 |archive-url=https://web.archive.org/web/20211009211251/https://www.nichd.nih.gov/health/topics/pcos/conditioninfo/diagnose |url-status=live }}</ref> Other conditions that produce similar symptoms include [[adrenal hyperplasia]], [[hypothyroidism]], and [[hyperprolactinemia|high blood levels of prolactin]].<ref name="NICHD How do health care providers diagnose PCOS?" />

=== Genetics ===
The genetic component appears to be inherited in an [[autosomal dominant]] fashion with high [[genetic penetrance]] but variable [[expressivity (genetics)|expressivity]] in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and, if a daughter receives the variant(s), the daughter will have the disease to some extent.<ref name="FertSter_molecular" /><ref name="pmid11212071" /><ref name="AnnNYAS_thoughts" /><ref name="OMIM" /> The genetic variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early [[baldness]] and/or excessive hair) and daughters, who will show signs of PCOS.<ref name="pmid11212071">{{cite journal |vauthors=Crosignani PG, Nicolosi AE |title=Polycystic ovarian disease: heritability and heterogeneity |journal=Human Reproduction Update |volume=7 |issue=1 |pages=3–7 |date=2001 |pmid=11212071 |doi=10.1093/humupd/7.1.3 |doi-access=free }}</ref><ref name="OMIM">{{cite web |url=http://omim.org/entry/184700 |website=[[OMIM]] |title=POLYCYSTIC OVARY SYNDROME 1; PCOS1 |access-date=15 November 2011 |publisher=McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine |vauthors=Hamosh A |date=12 September 2011 |url-status=live |archive-url=https://web.archive.org/web/20150716182537/http://omim.org/entry/184700 |archive-date=16 July 2015 }}</ref> The [[phenotype]] appears to manifest itself at least partially via heightened androgen levels secreted by [[theca of follicle|ovarian follicle theca]] cells from women with the allele.<ref name="AnnNYAS_thoughts">{{cite journal | vauthors = Strauss JF | title = Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome | journal = Annals of the New York Academy of Sciences | volume = 997 | issue = 1 | pages = 42–48 | date = November 2003 | pmid = 14644808 | doi = 10.1196/annals.1290.005 | s2cid = 23559461 | bibcode = 2003NYASA.997...42S }}</ref> The exact gene affected has not yet been identified.<ref name="Endo2006" /><ref name="FertSter_molecular" /><ref name="pmid15380142">{{cite journal | vauthors = Amato P, Simpson JL | title = The genetics of polycystic ovary syndrome | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 18 | issue = 5 | pages = 707–718 | date = October 2004 | pmid = 15380142 | doi = 10.1016/j.bpobgyn.2004.05.002 }}</ref> In rare instances, single-gene mutations can give rise to the syndrome phenotype.<ref>{{cite journal | vauthors = Draper N, Walker EA, Bujalska IJ, Tomlinson JW, Chalder SM, Arlt W, Lavery GG, Bedendo O, Ray DW, Laing I, Malunowicz E, White PC, Hewison M, Mason PJ, Connell JM, Shackleton CH, Stewart PM | title = Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency | journal = Nature Genetics | volume = 34 | issue = 4 | pages = 434–9 | date = August 2003 | pmid = 12858176 | doi = 10.1038/ng1214 | s2cid = 22772927 }}</ref> Current understanding of the pathogenesis of the syndrome suggests, however, that it is a complex multigenic disorder.<ref>{{cite journal | vauthors = Ehrmann DA | title = Polycystic ovary syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 12 | pages = 1223–36 | date = March 2005 | pmid = 15788499 | doi = 10.1056/NEJMra041536 | s2cid = 79796961 }}</ref>

The severity of PCOS symptoms appears to be largely determined by factors such as obesity.<ref name="Endo2006" /><ref name=BMC2010 /><ref name="pmid28416368">{{cite journal | vauthors = Faghfoori Z, Fazelian S, Shadnoush M, Goodarzi R | title = Nutritional management in women with polycystic ovary syndrome: A review study | journal = Diabetes & Metabolic Syndrome | volume = 11 | issue = Suppl 1 | pages = S429–S432 | date = November 2017 | pmid = 28416368 | doi = 10.1016/j.dsx.2017.03.030 | type = Review }}</ref> PCOS has some aspects of a [[metabolic disorder]], since its symptoms are partly reversible. Even though considered as a [[Gynaecology|gynecological]] problem, PCOS consists of 28 clinical symptoms.<ref>{{cite journal | vauthors = Witchel SF, Oberfield SE, Peña AS | title = Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls | journal = Journal of the Endocrine Society | volume = 3 | issue = 8 | pages = 1545–73 | date = August 2019 | pmid = 31384717 | pmc = 6676075 | doi = 10.1210/js.2019-00078 }}</ref>

Even though the name suggests that the ovaries are central to disease pathology, cysts are a symptom instead of the cause of the disease. Some symptoms of PCOS will persist even if both ovaries are removed; the disease can appear even if cysts are absent. Since its first description by Stein and Leventhal in 1935, the criteria of diagnosis, symptoms, and causative factors have been subject to debate. Gynecologists often see it as a gynecological problem, with the ovaries being the primary organ affected. However, recent insights show a multisystem disorder, with the primary problem lying in hormonal regulation in the [[hypothalamus]], with the involvement of many organs. The term PCOS is used because there is a wide spectrum of symptoms possible. It is common to have polycystic ovaries without having PCOS; approximately 20% of European women <!--Do not change this word to "people". 20% of women = 10% of people because 50% of people don't have ovaries at all.--> have polycystic ovaries, but most of those women do not have PCOS.<ref name="Dunaif2013" />

=== Environment ===
PCOS may be related to or worsened by exposures{{clarify|reason=Exposures to what?|date=November 2022}} during the [[Pregnancy|prenatal period]],<ref name="Hoeger-2014">{{cite journal | vauthors = Hoeger KM | title = Developmental origins and future fate in PCOS | journal = Seminars in Reproductive Medicine | volume = 32 | issue = 3 | pages = 157–8 | date = May 2014 | pmid = 24715509 | doi = 10.1055/s-0034-1371086 | s2cid = 32069697 }}</ref><ref name="Abbott-2005">{{cite journal | vauthors = Abbott DH, Barnett DK, Bruns CM, Dumesic DA | title = Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? | journal = Human Reproduction Update | volume = 11 | issue = 4 | pages = 357–374 |date= 2005 | pmid = 15941725 | doi = 10.1093/humupd/dmi013 | doi-access = free }}</ref><ref name="Rasgon-2004">{{cite journal | vauthors = Rasgon N | title = The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence | journal = Journal of Clinical Psychopharmacology | volume = 24 | issue = 3 | pages = 322–334 | date = June 2004 | pmid = 15118487 | doi = 10.1097/01.jcp.0000125745.60149.c6 | s2cid = 24603227 }}</ref> [[epigenetic]] factors, environmental impacts (especially industrial endocrine disruptors, such as [[bisphenol A]] and certain drugs)<ref name="Rutkowska-2014">{{cite journal | vauthors = Rutkowska A, Rachoń D | title = Bisphenol A (BPA) and its potential role in the pathogenesis of the polycystic ovary syndrome (PCOS) | journal = Gynecological Endocrinology | volume = 30 | issue = 4 | pages = 260–5 | date = April 2014 | pmid = 24397396 | doi = 10.3109/09513590.2013.871517 | s2cid = 5828672 }}</ref><ref name="Palioura-2013">{{cite journal | vauthors = Palioura E, Diamanti-Kandarakis E | title = Industrial endocrine disruptors and polycystic ovary syndrome | journal = Journal of Endocrinological Investigation | volume = 36 | issue = 11 | pages = 1105–11 | date = December 2013 | pmid = 24445124 | doi = 10.1007/bf03346762 | s2cid = 27141519 }}</ref><ref name="Hu-2011">{{cite journal | vauthors = Hu X, Wang J, Dong W, Fang Q, Hu L, Liu C | title = A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy | journal = Epilepsy Research | volume = 97 | issue = 1–2 | pages = 73–82 | date = November 2011 | pmid = 21820873 | doi = 10.1016/j.eplepsyres.2011.07.006 | s2cid = 26422134 }}</ref> and the increasing rates of obesity.<ref name="Palioura-2013" />

[[Endocrine disruptor]]s are defined as chemicals that can interfere with the [[endocrine system]] by mimicking hormones such as [[estrogen]]. According to the [[National Institutes of Health|NIH (National Institute of Health)]], examples of endocrine disruptors can include [[dioxins]] and [[triclosan]]. Endocrine disruptors can cause adverse health impacts in animals.<ref>{{Cite web |title=Endocrine Disruptors |url=https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm |access-date=10 November 2022 |website=National Institute of Environmental Health Sciences |language=en |archive-date=11 June 2020 |archive-url=https://web.archive.org/web/20200611191841/https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm |url-status=live }}</ref> Additional research is needed to assess the role that endocrine disruptors may play in disrupting reproductive health in women and possibly triggering or exacerbating PCOS and its related symptoms.<ref>{{cite journal | vauthors = Merkin SS, Phy JL, Sites CK, Yang D | title = Environmental determinants of polycystic ovary syndrome | journal = Fertility and Sterility | volume = 106 | issue = 1 | pages = 16–24 | date = July 2016 | pmid = 27240194 | doi = 10.1016/j.fertnstert.2016.05.011 | doi-access = free }}</ref>

The study of epigenetic changes in PCOS in utero or after birth has become an emerging area of research. While extensive research is not currently available, some studies are looking into the connection between abnormal DNA methylation changes in various tissues and the development of PCOS.<ref name=":4">{{Cite journal |last1=Liu |first1=Yan-Nan |last2=Qin |first2=Yi |last3=Wu |first3=Bin |last4=Peng |first4=Hui |last5=Li |first5=Ming |last6=Luo |first6=Hai |last7=Liu |first7=Lin- Lin |date=August 2022 |title=DNA methylation in polycystic ovary syndrome: Emerging evidence and challenges |url=https://linkinghub.elsevier.com/retrieve/pii/S0890623822000594 |journal=Reproductive Toxicology |language=en |volume=111 |pages=11–19 |doi=10.1016/j.reprotox.2022.04.010|pmid=35562068 |bibcode=2022RepTx.111...11L |doi-access=free }}</ref>  Environmental exposure to endocrine disruptors such as phthalates could alter DNA methylation patterns, particularly in the ovaries, granulosa cells, and adipose tissue.<ref name=":4" />

One study observed early embryonic development of mice subjected to di--(2-ethylhexyl) phthalate (DEHP) and the results showed abnormal methylation patterns in the Stra8 gene involved in meiosis initiation.<ref name=":5">{{Cite journal |last1=Zhang |first1=Teng |last2=Li |first2=Lan |last3=Qin |first3=Xun-Si |last4=Zhou |first4=Yang |last5=Zhang |first5=Xi-Feng |last6=Wang |first6=Lin-Qing |last7=De Felici |first7=Massimo |last8=Chen |first8=Hong |last9=Qin |first9=Guo-Qing |last10=Shen |first10=Wei |date=May 2014 |title=Di-(2-ethylhexyl) phthalate and bisphenol A exposure impairs mouse primordial follicle assembly in vitro |url=https://onlinelibrary.wiley.com/doi/10.1002/em.21847 |journal=Environmental and Molecular Mutagenesis |language=en |volume=55 |issue=4 |pages=343–353 |doi=10.1002/em.21847 |pmid=24458533 |bibcode=2014EnvMM..55..343Z |issn=0893-6692}}</ref> The gene for transcription factor Lhx8, involved in early follicular changes, was also impacted by DEHP when the neonatal mouse ovaries were analyzed. Together, these results showed DEHP induced epigenetic changes via DNA methylation to interfere with folliculogenesis, symptomatic of PCOS.<ref name=":5" /> Although DNA methylation in human embryonic development is not fully characterized, the animal model studies on epigenetic changes provide information to suggest that PCOS may have fetal origins.

Androgen excess is a central feature in the PCOS phenotype, and exposure in utero has shown PCOS-like features in adulthood. A study from 2014 induced DNA hypomethylation in the ovarian tissue of zebrafish exposed to androgens early in development.<ref name="ReferenceA">{{Cite journal |last1=Xu |first1=Ning |last2=Chua |first2=Angela K. |last3=Jiang |first3=Hong |last4=Liu |first4=Ning-Ai |last5=Goodarzi |first5=Mark O. |date=1 August 2014 |title=Early Embryonic Androgen Exposure Induces Transgenerational Epigenetic and Metabolic Changes |journal=Molecular Endocrinology |language=en |volume=28 |issue=8 |pages=1329–1336 |doi=10.1210/me.2014-1042 |pmid=24992182 |pmc=5414805 |issn=0888-8809}}</ref> Glucose homeostasis alterations were also observed. Furthermore, these effects were carried into the next generation, suggesting that epigenetic changes caused by excess androgens in the fetus could be transgenerational.<ref name="ReferenceA"/>